RORγ is a nuclear receptor which is important for the differentiation and activation of Th17 cells. RORγt is also known as a splice variant of RORγ (Nonpatent literature 1). RORγ and RORγt differ only in their N-terminal domains, and share the same ligand-binding domain and DNA-binding domain. It is reported that RORγ is expressed in other tissues besides Th17 cells (Nonpatent literature 1).
By inhibiting RORγ, the differentiation and activation of Th17 cells can be inhibited. IL-17 produced in Th17 cells is involved in the induction of a variety of chemokines, cytokines, metalloproteases and other inflammatory mediators, and the migration of neutrophil, hence, the inhibition of IL-17 may lead to the inhibition of such induction and migration (Nonpatent literatures 2 and 3).
RORγ in adipose tissues is related to the regulation of adipogenesis, and by inhibiting RORγ, insulin resistance can be improved (Nonpatent literature 4).
It is known that Th17 cells are involved in autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases; dry eye; and fibrosis such as pulmonary fibrosis and primary biliary cirrhosis. It is known that adipose tissues are involved in metabolic diseases.
As for rheumatoid arthritis, for example, it is reported that the administration of anti-IL-17 antibody can improve swelling and joint destruction associated with collagen-induced arthritis (Nonpatent literature 5). Moreover, it is reported that swelling and joint destruction associated with collagen-induced arthritis can be improved in experiments using IL-17-deficient mice (Nonpatent literature 6).
As for psoriasis, it is reported that in a clinical trial, the administration of anti-IL-17 antibody is effective in treating psoriasis (Nonpatent literature 7). Anti IL-17 antibodies have been placed on the market for use in psoriasis (Nonpatent literature 8).
As for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, in a colitis model induced by the adaptive transfer of T-cells, the adaptive transfer of T-cells derived from RORγ-KO mice does not increase IL-17 in the mucosa, thereby the onset of colitis can be suppressed (Nonpatent literature 9).
As for multiple sclerosis, the disease state of mouse experimental autoimmune encephalomyelitis model which is an animal model of multiple sclerosis can be suppressed in RORγt-KO mice (Nonpatent literature 10).
As for systemic lupus erythematosus, it is reported that the onset of GBM nephritis model which is an animal model of glomerulonephritis can be inhibited in RORγt-KO mice (Nonpatent literature 11). Nephritis associated with SLE may also be suppressed (Nonpatent literature 12).
As for ankylosing spondylitis, it is reported that the administration of anti-IL-17 antibody is effective in treating ankylosing spondylitis (Nonpatent literature 13).
As for uveitis, it is reported that the administration of anti-IL-17 antibody is effective in treating uveitis associated with Behcet's disease, sarcoidosis and Harada disease (Nonpatent literature 7).
As for polymyalgia rheumatica, an efficacy of anti-IL-17 antibody in treatment of polymyalgia rheumatica is currently tested in a clinical trial.
As for type I diabetes, the disease state of NOD mice which is a type I diabetes model can be suppressed by the administration of anti-IL-17 antibody (Nonpatent literature 14).
As for graft versus host disease, it is reported in a mouse transplant model that a survival rate and a rejection in a host would be improved by transfecting RORγKO mouse-derived cells (Nonpatent literature 19).
As for allergic disease such as asthma, in OVA-sensitized model, the attenuated eosinophilic pulmonary inflammation, the reduced numbers of CD4+ lymphocytes, and the decrease of Th2 cytokines/chemokines level are exhibited in RORγ-KO mice, that is, the allergenic reaction can be inhibited in RORγ-KO mice (Nonpatent literature 15).
As for dry eye, it is reported that the Th17 cells increases in an animal model of dry eye, and an efficacy of anti-IL-17 antibody in dry eye patient is currently tested in a clinical trial (Nonpatent literature 16).
As for fibrosis, in a bleomycin-induced pulmonary fibrosis model which is an animal model of pulmonary fibrosis, the administration of anti-IL-17 antibody can inhibit inflammation and fibrosis in lung and can increase survival of the animal (Nonpatent literature 17).
As for primary biliary cirrhosis, it is reported that Th17 cells in the lesion area of a patient with a primary biliary cirrhosis increase, and an efficacy of an antibody to IL-23 which activates Th17 cells is currently tested in a clinical trial (Nonpatent literature 18).
As for metabolic disease, the insulin resistance which is induced by feeding a high-fat diet can be suppressed in RORγ KO mice (Nonpatent literature 4).
On the basis of these findings, RORγ antagonists are thought to be useful for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, and graft versus host disease; allergic diseases such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic diseases such as diabetes.